Steroid, thyroid and retinoid hormones produce a diverse array of physiologic effects through the regulation of gene expression. Upon entering the cell, these hormones bind to a unique group of intracellular nuclear receptors which have been characterized as ligand-dependent transcription factors. This complex then moves into the nucleus where the receptor and its cognate ligand interact with the transcription preinitiation complex affecting its stability and ultimately the rate of transcription of the target genes. The interactions of the liganded receptor with the specific elements in the promoter region are mediated by two classes of molecules; corepressors which inhibit transactivation and coactivators which enhance transactivation.
SRC-3 (also known as steroid receptor coactivator-3, ACTR, RAC3, AIB-1 and p/CIP) is a member of the growing family of coactivators. Allelic variations of SRC-3 have been isolated by several labs and comparison of these sequences showed that they were all encoded by the same gene (Anzick et al., Science, 1997, 277, 965-968; Chen et al., Cell, 1997, 90, 569-580; Li et al., Proc. Natl. Acad. Sci. U.S.A., 1997, 94, 8479-8484; Torchia et al., Nature, 1997, 387, 677-684).
Like other coactivators, SRC-3 contains intrinsic histone acetyltransferase activity with a substrate preference for histones H3 and H4 (Chen et al., Cell, 1997, 90, 569-580). Studies of tissue distribution indicated that SRC-3 is found in most tissues with the highest expression in the heart, placenta, skeletal muscle and pancreas and low levels in the brain, lung, liver and kidney (Li and Chen, J. Biol. Chem., 1998, 273, 5948-5954).
SRC-3 expression has also been found to be substantial in several carcinoma cell lines. Investigations of breast and ovarian cancers revealed that SRC-3 was amplified and overexpressed in four of five estrogen receptor-positive breast and ovarian cancer cell lines as well as in breast biopsies (Anzick et al., Science, 1997, 277, 965-968).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of SRC-3. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting SRC-3 function. It is anticipated that antisense oligonucleotides against SRC-3 may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the effective and specific modulation of SRC-3 expression.